Carcinogenesis in various tissues is accompanied by alterations in protein and lipid glycosylation, such as changes in the expressions of Lewis histo-blood group antigens. Neoplastic transformation is often followed by changes in expression of one or more of these oligosaccharides in a pattern that is typical for the tissue. These alterations correlate with changes in the expressions of specific glycosyltransferases. Overexpression of Lewis antigens in some types of cancer might be a significant prognostic factor. Upregulation of Lewis(y), Lewis(b), and other alpha1,2-fucosylated oligosaccharides is linked to an increased tendency to metastasis and resistance to treatment. For example, invasive breast cancer of poor prognosis reveals high expression levels of Lewis(y) and Lewis(b). Lewis(x) is also overexpressed in breast cancer cells. Overexpression of Lewis(a) also occurs in precancerous states of stomach tissue. Upregulation of sialyl Lewis(a) correlates with the metastatic potential of colon and pancreatic malignancies and inversely with survival rate of patients. A similar relation was observed between sialyl Lewis(x) overexpression and malignancies of the lungs, prostate, urinary bladder, stomach, breast, kidney, and liver. Some of the Lewis antigens are ligands of specific receptors and adhesion molecules. For example, Lewis(x) is recognized by scavenger receptor C-type lectin (SRCL), which belongs to the group of innate immunity receptors. Sialyl Lewis(a) and sialyl Lewis(x) specifically interact with E- and P-selectins, which are key molecules in leukocyte rolling process. Ongoing research shows an increasing number of potential therapeutic applications related to the upregulation of Lewis antigens.